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Article ; Online: Comprehensive metabolic profiling of Geotrichum candidum and comparison with Saccharomyces cerevisiae.

Bamba, Takahiro / Hori, Yoshimi / Umebayashi, Kyohei / Soh, Chieko / Hakozaki, Tomohiro / Toyama, Kazumi / Osumi, Masako / Kondo, Akihiko / Hasunuma, Tomohisa

Journal of bioscience and bioengineering

2023 Volume 137, Issue 1, Page(s) 9–15

Abstract: Geotrichum candidum is a dimorphic yeast used in cheese processing. To our knowledge, no major metabolites have been identified to date in G. candidum except for some amino acid and fatty acid metabolites. This has limited research on the commercial use ... ...

Abstract	Geotrichum candidum is a dimorphic yeast used in cheese processing. To our knowledge, no major metabolites have been identified to date in G. candidum except for some amino acid and fatty acid metabolites. This has limited research on the commercial use of G. candidum. In this study, we aimed to analyze temporal changes in the intra- and extra-cellular metabolites of G. candidum and Saccharomyces cerevisiae cultured in YM medium as reference. As a result of metabolite analysis, it was observed that G. candidum tends to accumulate　pentose phosphate pathway compounds, which are involved in nucleic acid synthesis, after 48 h of cultivation when compared to S. cerevisiae. In addition, G. candidum accumulated higher amounts of the antioxidant glutathione in the medium than did S. cerevisiae. In addition, G. candidum accumulated large amounts of B vitamins such as pantothenic acid and nicotinic acid in the medium. Finally, we examined the potential of G. candidum as a host for the production of useful compounds such as pantothenic acid. When cultured in medium supplemented with the pantothenic acid precursor β-alanine, G. candidum produced 12-fold higher amounts of pantothenic acid (30 μM) than that by S. cerevisiae. This study indicates that G. candidum accumulates various useful compounds that are dissimilar to those produced by S. cerevisiae. Furthermore, G. candidum has the potential to produce useful chemicals under appropriate culture conditions.
MeSH term(s)	Saccharomyces cerevisiae ; Pantothenic Acid ; Cheese ; Amino Acids
Chemical Substances	Pantothenic Acid (19F5HK2737) ; Amino Acids
Language	English
Publishing date	2023-11-14
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1465387-4
ISSN	1347-4421 ; 1389-1723
ISSN (online)	1347-4421
ISSN	1389-1723
DOI	10.1016/j.jbiosc.2023.10.004
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Article ; Online: Characterization of vitamin B12 compounds from commercially available fish roe products

Yamanaka, Tamami / Namura, Mika / Koseki, Kyohei / Bito, Tomohiro / Umebayashi, Yukihiro / Watanabe, Fumio

Fish Sci. 2022 Nov., v. 88, no. 6 p.815-820

2022

Abstract: Although fish roes (or the egg-laden ovary) are seafood products with high nutritional value and are considered abundant in vitamins including vitamin B₁₂, nevertheless, the detailed properties of vitamin B₁₂ have not been fully elucidated in fish roe ... ...

Abstract	Although fish roes (or the egg-laden ovary) are seafood products with high nutritional value and are considered abundant in vitamins including vitamin B₁₂, nevertheless, the detailed properties of vitamin B₁₂ have not been fully elucidated in fish roe products. Vitamin B₁₂ content was determined using C18-reversed-phase high-performance liquid chromatography after purification of samples from immunoaffinity columns. Salmon egg-laden ovary products (sujiko), salmon roe products (ikura), dried mullet roe products (bottarga), and white sturgeon roe products (caviar) were found to contain substantial levels of vitamin B₁₂ (more than approximately 15 µg/100 g wet weight). Interestingly, high levels of vitamin B₁₂ per 100 g wet weight have been measured in pollack roe products (tarako) and flying fish roe products (tobiko). Liquid chromatography–electrospray-ionization/tandem mass spectrometry analysis revealed that vitamin B₁₂ was the predominant corrinoid in the evaluated fish roe products examined, while no inactive corrinoid compounds were identified. These results suggest that commercially available fish roe products could be an important source of vitamin B₁₂ for use as a dietary product for humans.
Keywords	Acipenser transmontanus ; fish roe ; high performance liquid chromatography ; mass spectrometry ; mullet ; nutritive value ; pollock ; salmon ; seafoods ; vitamin B12
Language	English
Dates of publication	2022-11
Size	p. 815-820.
Publishing place	Springer Japan
Document type	Article ; Online
ZDB-ID	1192654-5
ISSN	1444-2906 ; 0919-9268
ISSN (online)	1444-2906
ISSN	0919-9268
DOI	10.1007/s12562-022-01636-8
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Article: The roles of ubiquitin and lipids in protein sorting along the endocytic pathway.

Umebayashi, Kyohei

Cell structure and function

2003 Volume 28, Issue 5, Page(s) 443–453

Abstract: After cell surface receptors are internalized for endocytosis, they are accurately sorted in endosomes. Some are recycled to the plasma membrane and others are downregulated by delivery to lysosomes. Evidence is rapidly accumulating that ubiquitination ... ...

Abstract	After cell surface receptors are internalized for endocytosis, they are accurately sorted in endosomes. Some are recycled to the plasma membrane and others are downregulated by delivery to lysosomes. Evidence is rapidly accumulating that ubiquitination of cargo proteins acts as a sorting signal during endocytosis. Sorting devices that recognize ubiquitin are distributed to various compartments, probably acting in a concerted manner. Cholesterol is enriched in the plasma membrane and endosomes, and is involved in protein sorting by forming microdomains called lipid rafts. Ubiquitin and cholesterol hold the key to control the endocytic sorting, and they are likely acting cooperatively.
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Cholesterol/metabolism ; Endocytosis/physiology ; Endosomes/metabolism ; Golgi Apparatus/metabolism ; Lipid Metabolism ; Membrane Microdomains/metabolism ; Protein Sorting Signals ; Protein Transport ; Ubiquitin/metabolism
Chemical Substances	Protein Sorting Signals ; Ubiquitin ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2003-11-05
Publishing country	Japan
Document type	Journal Article ; Review
ZDB-ID	197293-5
ISSN	0386-7196
ISSN	0386-7196
DOI	10.1247/csf.28.443
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Article ; Online: Distribution and functions of sterols and sphingolipids.

Hannich, J Thomas / Umebayashi, Kyohei / Riezman, Howard

Cold Spring Harbor perspectives in biology

2011 Volume 3, Issue 5

Abstract: Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than sterols. Both sterols and sphingolipids differ in their structural features in vertebrates, ... ...

Abstract	Sterols and sphingolipids are considered mainly eukaryotic lipids even though both are present in some prokaryotes, with sphingolipids being more widespread than sterols. Both sterols and sphingolipids differ in their structural features in vertebrates, plants, and fungi. Interestingly, some invertebrates cannot synthesize sterols de novo and seem to have a reduced dependence on sterols. Sphingolipids and sterols are found in the plasma membrane, but we do not have a clear picture of their precise intracellular localization. Advances in lipidomics and subcellular fractionation should help to improve this situation. Genetic approaches have provided insights into the diversity of sterol and sphingolipid functions in eukaryotes providing evidence that these two lipid classes function together. Intermediates in sphingolipid biosynthesis and degradation are involved in signaling pathways, whereas sterol structures are converted to hormones. Both lipids have been implicated in regulating membrane trafficking.
MeSH term(s)	Animals ; Cell Fractionation ; Cell Membrane/metabolism ; Models, Biological ; Signal Transduction ; Sphingolipids/biosynthesis ; Sphingolipids/metabolism ; Sphingolipids/physiology ; Sterols/biosynthesis ; Sterols/metabolism
Chemical Substances	Sphingolipids ; Sterols
Language	English
Publishing date	2011-05-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a004762
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Article ; Online: Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation.

Umebayashi, Kyohei / Stenmark, Harald / Yoshimori, Tamotsu

Molecular biology of the cell

2008 Volume 19, Issue 8, Page(s) 3454–3462

Abstract: c-Cbl is the E3 ubiquitin ligase that ubiquitinates the epidermal growth factor (EGF) receptor (EGFR). On the basis of localization, knockdown, and in vitro activity analyses, we have identified the E2 ubiquitin-conjugating enzyme that cooperates with c- ... ...

Abstract	c-Cbl is the E3 ubiquitin ligase that ubiquitinates the epidermal growth factor (EGF) receptor (EGFR). On the basis of localization, knockdown, and in vitro activity analyses, we have identified the E2 ubiquitin-conjugating enzyme that cooperates with c-Cbl as Ubc4/5. Upon EGF stimulation, both Ubc4/5 and c-Cbl were relocated to the plasma membrane and then to Hrs-positive endosomes, strongly suggesting that EGFR continues to be ubiquitinated after internalization. Our time-course experiment showed that EGFR undergoes polyubiquitination, which seemed to be facilitated during the transport to Hrs-positive endosomes. Use of a conjugation-defective ubiquitin mutant suggested that receptor polyubiquitination is required for efficient interaction with Hrs and subsequent sorting to lysosomes. Abrupt inhibition of the EGFR kinase activity resulted in dissociation of c-Cbl from EGFR. Concomitantly, EGFR was rapidly deubiquitinated and its degradation was delayed. We propose that sustained tyrosine phosphorylation of EGFR facilitates its polyubiquitination in endosomes and counteracts rapid deubiquitination, thereby ensuring Hrs-dependent lysosomal sorting.
MeSH term(s)	Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Endocytosis ; Endosomes/metabolism ; ErbB Receptors/metabolism ; Gene Expression Regulation ; HeLa Cells ; Humans ; Models, Biological ; Proto-Oncogene Proteins c-cbl/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Conjugating Enzymes/physiology ; Ubiquitination
Chemical Substances	UBE2D2 protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Proto-Oncogene Proteins c-cbl (EC 2.3.2.27) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2008-05-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E07-10-0988
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Zs.A 2853: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Ergosterol is required for targeting of tryptophan permease to the yeast plasma membrane.

Umebayashi, Kyohei / Nakano, Akihiko

The Journal of cell biology

2003 Volume 161, Issue 6, Page(s) 1117–1131

Abstract: It was known that the uptake of tryptophan is reduced in the yeast erg6 mutant, which is defective in a late step of ergosterol biosynthesis. Here, we show that this is because the high affinity tryptophan permease Tat2p is not targeted to the plasma ... ...

Abstract	It was known that the uptake of tryptophan is reduced in the yeast erg6 mutant, which is defective in a late step of ergosterol biosynthesis. Here, we show that this is because the high affinity tryptophan permease Tat2p is not targeted to the plasma membrane. In wild-type cells, the plasma membrane localization of Tat2p is regulated by the external tryptophan concentration. Tat2p is transported from the Golgi apparatus to the vacuole at high tryptophan, and to the plasma membrane at low tryptophan. However, in the erg6 mutant, Tat2p is missorted to the vacuole at low tryptophan. The plasma membrane targeting of Tat2p is dependent on detergent-insoluble membrane domains, suggesting that sterol affects the sorting through the organization of lipid rafts. The erg6 mutation also caused missorting to the multivesicular body pathway in late endosomes. Thus, sterol composition is crucial for protein sorting late in the secretory pathway. Tat2p is subject to polyubiquitination, which acts as a vacuolar-targeting signal, and the inhibition of this process suppresses the Tat2p sorting defects of the erg6 mutant. The sorting mechanisms of Tat2p that depend on both sterol and ubiquitin will be discussed.
MeSH term(s)	Amino Acid Transport Systems/metabolism ; Cell Membrane/enzymology ; Cells, Cultured ; Endosomes/metabolism ; Ergosterol/metabolism ; Membrane Microdomains/enzymology ; Mutation/genetics ; Protein Structure, Tertiary/genetics ; Protein Transport/genetics ; Saccharomyces cerevisiae/cytology ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Transport Vesicles/enzymology ; Tryptophan/metabolism ; Ubiquitin/metabolism ; Vacuoles/enzymology
Chemical Substances	Amino Acid Transport Systems ; Saccharomyces cerevisiae Proteins ; TAT2 protein, S cerevisiae ; Ubiquitin ; Tryptophan (8DUH1N11BX) ; Ergosterol (Z30RAY509F)
Language	English
Publishing date	2003-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.200303088
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Article ; Online: Molecular dissection of internalization of Porphyromonas gingivalis by cells using fluorescent beads coated with bacterial membrane vesicle.

Tsuda, Kayoko / Amano, Atsuo / Umebayashi, Kyohei / Inaba, Hiroaki / Nakagawa, Ichiro / Nakanishi, Yoshinobu / Yoshimori, Tamotsu

Cell structure and function

2005 Volume 30, Issue 2, Page(s) 81–91

Abstract: Porphyromonas gingivalis is one of the causative agents of adult periodontitis, and has been reported to be internalized by nonphagocytic epithelial cells. However, the mechanism for the internalization remains unclear. In the present study, we addressed ...

Abstract	Porphyromonas gingivalis is one of the causative agents of adult periodontitis, and has been reported to be internalized by nonphagocytic epithelial cells. However, the mechanism for the internalization remains unclear. In the present study, we addressed this issue using fluorescent beads coated with bacterial membrane vesicles (MVs) that retain surface components of P. gingivalis. We established an assay system in which we could easily quantify the bead internalization to cells. MVs-coated beads were internalized by HeLa cells in kinetics similar to that of living bacteria. The internalization depended on dynamin but not clathrin. The beads were internalized through the actin-mediated pathway that is controlled by phosphatidylinositol (PI) 3-kinase. The dynamics of microtubule assembly and disassembly was also required. Further, the treatment of cells with cholesterol-binding reagents significantly inhibited bead internalization, and the internalized beads were apparently colocalized with ganglioside GM1 and caveolin-1, which suggest the involvement of the lipid raft in the process. These results suggest that P. gingivalis accomplishes its internalization utilizing membrane lipid raft and cytoskeletal functions of the target cells.
MeSH term(s)	Actin Cytoskeleton/physiology ; Actins/metabolism ; Adaptor Proteins, Signal Transducing ; Androstadienes/pharmacology ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Calcium-Binding Proteins/genetics ; Calcium-Binding Proteins/physiology ; Caveolin 1/analysis ; Cell Membrane/physiology ; Chromones/pharmacology ; Clathrin/physiology ; Cytochalasin D/pharmacology ; Dynamin II/physiology ; Endocytosis ; Filipin/pharmacology ; Fluorescent Dyes ; G(M1) Ganglioside/analysis ; HeLa Cells/microbiology ; HeLa Cells/physiology ; Humans ; Intracellular Signaling Peptides and Proteins ; Membrane Lipids/physiology ; Membrane Microdomains/drug effects ; Membrane Microdomains/physiology ; Microtubules/drug effects ; Microtubules/physiology ; Morpholines/pharmacology ; Nocodazole/pharmacology ; Nystatin/pharmacology ; Paclitaxel/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/physiology ; Phosphoproteins/genetics ; Phosphoproteins/physiology ; Porphyromonas gingivalis/chemistry ; Porphyromonas gingivalis/ultrastructure ; Recombinant Fusion Proteins/physiology ; Sequence Deletion ; Thiazoles/pharmacology ; Thiazolidines ; Tubulin/metabolism ; Wortmannin
Chemical Substances	Actins ; Adaptor Proteins, Signal Transducing ; Androstadienes ; Bridged Bicyclo Compounds, Heterocyclic ; Calcium-Binding Proteins ; Caveolin 1 ; Chromones ; Clathrin ; EPS15 protein, human ; Fluorescent Dyes ; Intracellular Signaling Peptides and Proteins ; Membrane Lipids ; Morpholines ; Phosphoproteins ; Recombinant Fusion Proteins ; Thiazoles ; Thiazolidines ; Tubulin ; Nystatin (1400-61-9) ; Cytochalasin D (22144-77-0) ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; G(M1) Ganglioside (37758-47-7) ; Filipin (87Z59R7D14) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Dynamin II (EC 3.6.5.5) ; Paclitaxel (P88XT4IS4D) ; Nocodazole (SH1WY3R615) ; latrunculin A (SRQ9WWM084) ; Wortmannin (XVA4O219QW)
Language	English
Publishing date	2005-12-08
Publishing country	Japan
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	197293-5
ISSN	1347-3700 ; 0386-7196
ISSN (online)	1347-3700
ISSN	0386-7196
DOI	10.1247/csf.30.81
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Article: Roles of O-mannosylation of aberrant proteins in reduction of the load for endoplasmic reticulum chaperones in yeast.

Nakatsukasa, Kunio / Okada, Shigeo / Umebayashi, Kyohei / Fukuda, Ryoichi / Nishikawa, Shuh-Ichi / Endo, Toshiya

The Journal of biological chemistry

2004 Volume 279, Issue 48, Page(s) 49762–49772

Abstract: The protein quality control system in the endoplasmic reticulum (ER) ensures that only properly folded proteins are deployed throughout the cells. When nonnative proteins accumulate in the ER, the unfolded protein response is triggered to limit further ... ...

Abstract	The protein quality control system in the endoplasmic reticulum (ER) ensures that only properly folded proteins are deployed throughout the cells. When nonnative proteins accumulate in the ER, the unfolded protein response is triggered to limit further accumulation of nonnative proteins and the ER is cleared of accumulated nonnative proteins by the ER-associated degradation (ERAD). In the yeast ER, aberrant nonnative proteins are mainly directed for the ERAD, but a distinct fraction of them instead receive O-mannosylation. In order to test whether O-mannosylation might also be a mechanism to process aberrant proteins in the ER, here we analyzed the effect of O-mannosylation on two kinds of model aberrant proteins, a series of N-glycosylation site mutants of prepro-alpha-factor and a pro-region-deleted derivative of Rhizopus niveus aspartic proteinase-I (Deltapro) both in vitro and in vivo. O-Mannosylation increases solubilities of the aberrant proteins and renders them less dependent on the ER chaperone, BiP, for being soluble. The release from ER chaperones allows the aberrant proteins to exit out of the ER for the normal secretory pathway transport. When the gene for Pmt2p, responsible for the O-mannosylation of these aberrant proteins, and that for the ERAD were simultaneously deleted, the cell exhibited enhanced unfolded protein response. O-Mannosylation may therefore function as a fail-safe mechanism for the ERAD by solubilizing the aberrant proteins that overflowed from the ERAD pathway and reducing the load for ER chaperones.
MeSH term(s)	Endoplasmic Reticulum/metabolism ; Gene Deletion ; Glycosylation ; Mannose/metabolism ; Mannosyltransferases/genetics ; Mannosyltransferases/metabolism ; Microsomes/metabolism ; Molecular Chaperones/metabolism ; Temperature ; Yeasts/metabolism
Chemical Substances	Molecular Chaperones ; Mannosyltransferases (EC 2.4.1.-) ; protein O-mannosyltransferase (EC 2.4.1.109) ; Mannose (PHA4727WTP)
Language	English
Publishing date	2004-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M403234200
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Article: Intracellular inclusions containing mutant alpha1-antitrypsin Z are propagated in the absence of autophagic activity.

Kamimoto, Takahiro / Shoji, Shisako / Hidvegi, Tunda / Mizushima, Noboru / Umebayashi, Kyohei / Perlmutter, David H / Yoshimori, Tamotsu

The Journal of biological chemistry

2005 Volume 281, Issue 7, Page(s) 4467–4476

Abstract: Mutant alpha(1)-antitrypsin Z (alpha(1)-ATZ) protein, which has a tendency to form aggregated polymers as it accumulates within the endoplasmic reticulum of the liver cells, is associated with the development of chronic liver injury and hepatocellular ... ...

Abstract	Mutant alpha(1)-antitrypsin Z (alpha(1)-ATZ) protein, which has a tendency to form aggregated polymers as it accumulates within the endoplasmic reticulum of the liver cells, is associated with the development of chronic liver injury and hepatocellular carcinoma in hereditary alpha(1)-antitrypsin (alpha(1)-AT) deficiency. Previous studies have suggested that efficient intracellular degradation of alpha(1)-ATZ is correlated with protection from liver disease in alpha(1)-AT deficiency and that the ubiquitin-proteasome system accounts for a major route, but not the sole route, of alpha(1)-ATZ disposal. Yet another intracellular degradation system, autophagy, has also been implicated in the pathophysiology of alpha(1)-AT deficiency. To provide genetic evidence for autophagy-mediated disposal of alpha(1)-ATZ, here we used cell lines deleted for the Atg5 gene that is necessary for initiation of autophagy. In the absence of autophagy, the degradation of alpha(1)-ATZ was retarded, and the characteristic cellular inclusions of alpha(1)-ATZ accumulated. In wild-type cells, colocalization of the autophagosomal membrane marker GFP-LC3 and alpha(1)-ATZ was observed, and this colocalization was enhanced when clearance of autophagosomes was prevented by inhibiting fusion between autophagosome and lysosome. By using a transgenic mouse with liver-specific inducible expression of alpha(1)-ATZ mated to the GFP-LC3 mouse, we also found that expression of alpha(1)-ATZ in the liver in vivo is sufficient to induce autophagy. These data provide definitive evidence that autophagy can participate in the quality control/degradative pathway for alpha(1)-ATZ and suggest that autophagic degradation plays a fundamental role in preventing toxic accumulation of alpha(1)-ATZ.
MeSH term(s)	Animals ; Autophagy ; Autophagy-Related Protein 5 ; Cells, Cultured ; Endoplasmic Reticulum/metabolism ; Inclusion Bodies/metabolism ; Mice ; Microtubule-Associated Proteins/physiology ; Mutation ; alpha 1-Antitrypsin/metabolism
Chemical Substances	Atg5 protein, mouse ; Autophagy-Related Protein 5 ; Microtubule-Associated Proteins ; alpha 1-Antitrypsin
Language	English
Publishing date	2005-12-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M509409200
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Article: Endothelial nitric-oxide synthase antisense (NOS3AS) gene encodes an autophagy-related protein (APG9-like2) highly expressed in trophoblast.

Yamada, Takahiro / Carson, Andrew R / Caniggia, Isabella / Umebayashi, Kyohei / Yoshimori, Tamotsu / Nakabayashi, Kazuhiko / Scherer, Stephen W

The Journal of biological chemistry

2005 Volume 280, Issue 18, Page(s) 18283–18290

Abstract: Macroautophagy is an intracellular degradation system for the majority of proteins and some organelles that is conserved in all eukaryotic species. The precise role of autophagy in mammalian development and potential involvement in disease remain to be ... ...

Abstract	Macroautophagy is an intracellular degradation system for the majority of proteins and some organelles that is conserved in all eukaryotic species. The precise role of autophagy in mammalian development and potential involvement in disease remain to be discerned. Yeast Atg9p is the first integral membrane protein shown to be essential for the cytoplasm to vacuole targeting (Cvt) pathway and autophagy, whereas its mammalian functional orthologue has yet to be identified. We have identified two human genes homologous to yeast Atg9p and designated these as APG9L1 and APG9L2. We have previously identified APG9L2 as NOS3AS, which participates in the post-transcriptional regulation of the endothelial nitric-oxide synthase (NOS3) gene on chromosome 7 through its antisense overlap. In human adult tissues, APG9L1 was ubiquitously expressed, whereas APG9L2 was highly expressed in placenta (trophoblast cells) and pituitary gland. In transient transfection assays we found that both proteins were primarily localized to the perinuclear region and also scattered throughout the cytosol as dots, a subset of which colocalized with an autophagosome-specific marker LC3 under starvation conditions. Finally, by the small interfering RNA-mediated knockdown of APG9L1 in HeLa cells, we demonstrated that APG9L1 is essential for starvation-induced autophagosome formation. In addition, APG9L2 can functionally complement APG9L1 in this process. These results, taken together with those of phylogenetic and sequence analyses, suggest that both APG9L1 and APG9L2 are functionally orthologous to the yATG9 in autophagosome formation. Moreover, APG9L2 is a vertebrate-specific gene that may have gained critical roles in mammalian-specific developmental events, such as placentation, through rapid evolution.
MeSH term(s)	Animals ; Antisense Elements (Genetics)/biosynthesis ; Antisense Elements (Genetics)/genetics ; Autophagy/genetics ; Autophagy/physiology ; Autophagy-Related Proteins ; Chickens ; Dogs ; Drosophila melanogaster ; Gene Expression Regulation, Developmental ; HeLa Cells ; Humans ; Membrane Proteins/biosynthesis ; Membrane Proteins/genetics ; Mice ; Molecular Sequence Data ; Nitric Oxide Synthase/biosynthesis ; Nitric Oxide Synthase/genetics ; Nitric Oxide Synthase Type II ; Nitric Oxide Synthase Type III ; Pan troglodytes ; Rats ; Saccharomyces cerevisiae ; Takifugu ; Trophoblasts/enzymology ; Zebrafish
Chemical Substances	ATG9B protein, human ; Antisense Elements (Genetics) ; Atg9b protein, mouse ; Autophagy-Related Proteins ; Membrane Proteins ; NOS3 protein, human (EC 1.14.13.39) ; Nitric Oxide Synthase (EC 1.14.13.39) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; Nos3 protein, mouse (EC 1.14.13.39) ; Nos3 protein, rat (EC 1.14.13.39)
Language	English
Publishing date	2005-03-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M413957200
Database	MEDical Literature Analysis and Retrieval System OnLINE

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